CN101023922A

CN101023922A - Anti-cancer slow-release agent carried with glucocorticoid hormone and chemical therapy medicine

Info

Publication number: CN101023922A
Application number: CNA2006102013995A
Authority: CN
Inventors: 孔庆忠; 邹会凤; 刘恩祥; 苏红清
Original assignee: Jinan Kangquan Medicine Science and Technology Co Ltd
Current assignee: Jinan Kangquan Medicine Science and Technology Co Ltd
Priority date: 2006-12-26
Filing date: 2006-12-26
Publication date: 2007-08-29

Abstract

The present invention relates to a anti-cancer slow-release preparation containing glucocorticoid and chemotherapeutic medicine. Said anti-cancer slow-release preparation is a slow-release injection formed from slow-release microsphere and solvent. The slow-release microsphere includes anti-cancer effective component and slow-release auxiliary material, its solvent is a special solvent containing suopension adjuvant. The glucocorticoid is selected from prednisolone, methyl prednisolone, dexamethasone, betamethasone, triamcinolone and triamcinolone acetonide, its chemotherapeutic medicine is selected from phosphoinositide 3-kinase inhibitor and pyrimidine analogues. The slow-release auxiliary material is polylactic acid and its copolymer, polyethylene glycol, carboxyl-terminated polylactic acid copolymer, difatty acid and sebacic acid copolymer, poly (erucidic acid dimer-sebacic acid) and poly (fumaric acid-sebacic acid) biological compatibility macromolecule, and the suspension adjuvant is selected from carboxymethylcellulose sodium, etc. Said invention also can be made into slow-release implantation preparation.

Description

Anti-cancer sustained-release agent carrying glucocorticoid hormone and chemotherapeutic drug

(I) technical field

The invention relates to an anticancer sustained release agent containing glucocorticoid and chemotherapy drugs, belonging to the technical field of drugs. Specifically, the invention provides a slow release injection and a slow release implant containing glucocorticoid. The anticancer sustained release agent can effectively inhibit or destroy solid tumor stroma and tumor blood vessel, inhibit tumor neovascularization, effectively reduce tension, interstitial pressure and interstitial viscosity in tumor, further improve interstitial fluid conductivity, facilitate drug to enter solid tumor and effectively diffuse in tumor, and increase drug sensitivity.

(II) background of the invention

Traditional chemotherapy has no selectivity, is difficult to form effective drug concentration or therapeutic dose locally on the tumor, has poor effect and high toxicity, and is limited by systemic toxicity reaction when the drug or radiation dose is simply increased. See, e.g., "Intratumoral Placement of cisplatin plus systemic Carmustine to treat rat brain tumors" [ J.Otsugaku "69, pp.76-82, 1998 (Kong Q et al, J SurgOnco1.1998 Oct; 69 (2): 76-82).

Low dose anti-cancer drug therapy can not only increase drug tolerance of cancer cells, but also promote invasive growth thereof, see Beam et al, "anti-cancer drug pulsed screening increases drug tolerance and in vitro infiltration capacity of human lung cancer cells with concomitant changes in gene expression" [ International journal of cancer (Liang Y, et al, Int Jcancer. 2004; 111 (4): 484-93) ].

The local placement of the antitumor drug can better overcome the defects, not only can obviously improve the local drug concentration of the tumor, but also can obviously reduce the systemic toxic reaction. A number of in vitro and in vivo experiments have shown therapeutic efficacy against solid tumors, see Kongqing et al, "cisplatin placement in tumors plus systemic carmustine for treatment of rat brain tumors" [ J.Oncork.69, 76-82 ], 1998 (Kong Q et al, J Surg Oncol.1998 Oct; 69 (2): 76-82) ] and Kongqing et al, "cisplatin placement in tumors for cure of rat primary brain tumors" [ J.Oncork.64, 268-273 (1997) (Kong Q et al, JSURg Oncol.1997 Oct; 64: 268-273). See also Chinese patent (ZL 00111093.4; ZL 96115937.5; application Nos. 001111264, 001111272) and U.S. patent Nos. 6,376,525B 1; 5,651,986; 5,626,862).

However, solid tumors are composed of tumor cells and tumor stroma, wherein blood vessels in the tumor stroma not only provide a scaffold and essential nutrients for the growth of tumor cells, but also influence the penetration and diffusion of chemotherapeutic drugs around tumors and in tumor tissues, see Niti et al, "influence of extracellular stroma conditions on drug transport in solid tumors" [ Cancer research ] No. 60, No. 2497, No. 503, 2000 (Netti PA, Cancer Res.2000, No. 60 (9): 2497, No. 503).

The components of fibrin and collagen in blood vessels and connective tissues in tumor stroma and hyperproliferative tumor cells cause high interstitial pressure (interstitial pressure), high interstitial viscosity (interstitial viscosity), high tissue tension coefficient (tissue tension module) and low interstitial fluid conductivity (hydralic con) of solid tumors. These factors greatly limit the effective diffusion of drugs into solid tumors and within tumors, and thus constitute a major obstacle to tumor chemotherapy.

Moreover, the blood vessels in the tumor stroma are insensitive to conventional chemotherapeutic drugs, often resulting in increased resistance of tumor cells to anticancer drugs, and local chemotherapy often is complicated by local edema, with consequent failure of treatment.

Disclosure of the invention

Aiming at the defects of the prior art, the invention provides a novel pharmaceutical composition which contains glucocorticoid and anticancer drugs. More particularly, the sustained-release preparation is a sustained-release preparation for resisting solid tumors, mainly a sustained-release implant and a sustained-release injection. The local application can effectively inhibit or destroy blood vessels of the tumor and can inhibit the new blood vessels of the tumor; can inhibit tumor growth and increase the sensitivity of tumor cells to anticancer drugs; the sustained release agent for resisting solid tumor can effectively reduce tension, interstitial pressure and interstitial viscosity in tumor, thereby improving interstitial fluid conductivity, and facilitating the drug to enter solid tumor and effectively diffuse in tumor.

In addition, the glucocorticoid and the anticancer drug are prepared into the sustained release preparation (mainly a sustained release injection and a sustained release implant), which not only can greatly improve the drug concentration of the local tumor, reduce the drug concentration of the drug in the circulatory system and reduce the toxicity of the drug to normal tissues, but also can greatly facilitate the drug injection, reduce the complications of the operation and reduce the cost of patients. The anticancer medicine can inhibit tumor growth and raise the sensitivity of tumor cell to anticancer medicine. The above unexpected findings constitute the subject of the present invention.

The anti-solid tumor sustained release agent comprises an anti-cancer active ingredient and a pharmaceutic adjuvant, wherein the anti-cancer active ingredient comprises a chemotherapeutic drug and glucocorticoid selected from a phosphoinositide 3-kinase (PI3K) inhibitor, a pyrimidine analogue and/or a DNA repair enzyme inhibitor; the glucocorticoid has the function of inhibiting the growth of tumor cells, can effectively inhibit or destroy tumor blood vessels and inhibit the formation of tumor neovessels, thereby not only leading the tumor cells to lose the sources of the stent and nutrient substances required by the growth, but also obviously promoting the penetration and the diffusion of chemotherapeutic drugs into tumors, the periphery of the tumors and the tumor tissues. The glucocorticoid also effectively reduces the tension, interstitial pressure and interstitial viscosity in the tumor, thereby improving the interstitial fluid conductivity of the glucocorticoid and facilitating the penetration and diffusion of the drug into solid tumors, the tumor periphery and the tumor tissues.

Glucocorticoids, including, but not limited to, cortisone (cortisone), hydrocortisone (hydrocortisone), hydrocortisone acetate (hydrocortisone acetate), hydrocortisone butyrate (hydrocortisone butyrate), Prednisone (Prednisone), prednisolone (Prednisone), Methylprednisolone (Methylprednisolone), Triamcinolone (Triamcinolone Acetonide, Triamcinolone, Triamcinolone flupredone, Triamcinolone Acetonide, Triamcinolone aceton, Betamethasone dipropionate (betamethasone), fluocinolone (flucinode), clobetasone (Halcinonide )), halometasone (halmethasone), Beclomethasone Dipropionate (BDP), Budesonide (BUD) and fluticasone.

Glucocorticoids also include salts and esters that may be used, such as, but not limited to, acetic acid, butyric acid, sodium succinate, diacetate, phosphoric acid, propionic acid, hydrochloride or ester, and the like.

The glucocorticoid medicaments are classified into low, medium and high efficiency according to the strength of the effect, generally thought that the low efficiency mainly comprises cortisone and hydrocortisone, and the daily dosage is about 1-50 mg; the intermediate effect mainly comprises prednisone, prednisolone, methylprednisolone and triamcinolone, and the daily dosage is 0.1-10 mg; the high efficiency mainly comprises betamethasone and dexamethasone, and the daily dose is 0.01-5 mg.

The invention is selected according to the clinical dosage, and the clinical dosage is divided into the following categories (1) low-efficiency category: including, but not limited to, cortisone, hydrocortisone acetate, prednisone; (2) the intermediate efficiency class: including, but not limited to, prednisolone, methylprednisolone, clobetasone butyrate, hydrocortisone butyrate, dexamethasone, betamethasone, triamcinolone acetonide, mometasone furoate, fluocinolone acetonide; (3) high-efficiency class: including, but not limited to, flumethasone pivalate, desatasone valerate, betamethasone dipropionate, clobetasone, halometasone, beclomethasone dipropionate, budesonide, fluticasone.

The dosage of the glucocorticoid medicaments is determined according to specific situations, and the daily dosage of low-efficiency medicaments is about 1-50mg when the glucocorticoid medicaments are used in a clinical system; the daily dosage of the intermediate effect is 0.1-10 mg; the daily dose of the composition is 0.01-5 mg. The amount of the present invention may be, but is not limited to, 0.1 to 10 times, preferably 0.1 to 5 times, the daily amount as mentioned above.

Glucocorticoids also include their salts such as, but not limited to, sulfate, phosphate, hydrochloride, lactobionate, acetate, aspartate, nitrate, citrate, purine or pyrimidine salts, succinate, maleate and the like.

Phosphoinositide 3-kinase (abbreviated PI3K) inhibitors are selected from one or a combination of the following: 7-hydroxy-astrosporin, 7-O-alkyl-astrosporin, beta-methoxyastrosporin, alkylphosphocholine, hexadecylphosphocholine, octadecyl- (1, 1-dimethyl-4-piperidine) phosphate, 1-O-hexadecyl-2-O-methyl-rac-propanetriyl-3-phosphocholine, 1-O-octadecyl-2-O-methyl-sn-propanetriyl-3-phosphocholine, inositol polyphosphate, tetradecyl phosphocholine, hexadecyl (N-N-N-trimethyl) hexanolamine, hexakis (N-N-trimethyl) hexanolamine, alpha-methoxyastrosporin, alkylphosphocholine, hexadecyl phosphocholine, octadecyl-2-O-methyl-rac-propanetriyl-3-phosphocholine, 1-O-octadecyl-3-phosphocholine, 1, Octadecyl phosphorylcholine or octadecyl- [2- (N-methylpiperidine) ethyl ] -phosphate. Among them, 7-hydroxy-astrosporin, 7-O-alkyl-astrosporin, beta-methoxyastrosporin, alkylphosphocholine, and hexadecylphosphocholine are preferable.

The pyrimidine analogue is mainly selected from one or more of O4-benzyl folic acid, 2, 4, 5-triamino-6-benzyloxy pyrimidine, 2, 4-diamino-6-benzyloxy-5-nitrosopyrimidine, 2, 4-diamino-6-benzyloxy-5-bromo pyrimidine, 2-amino-4-benzyloxy-5-nitropyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitropyrimidine, 2, 4-diamino-6-benzyloxy-s-triazine and 2-amino-O4-benzyl pteridine.

The DNA repair enzyme inhibitor can be any one of DNA-dependent protein kinase inhibitor and/or poly (ADP-ribose) polymerase inhibitor, but is selected from imidazopiperazine, imidazopyridine, wortmannin, benzopyran, 6-aryl-2-morphinan-4-yl-pyran-4-yl, 2- (4-morpholino) -8-phenylchromone, 7-ethyl-10-hydroxycamptothecin, 3-cyano-6-hydrazonomethyl-5- (4-pyridyl) pyridine- [1H ]2-1, phenylbutyric acid, methoxyamine, hydroxylamine, inositol polyphosphate, tetradecyl phosphorylcholine, hexakis (N-N-trimethyl) hexanolamine, and mixtures thereof, Octadecylphosphocholine, octadecyl- [2- (N-methylpiperidine) ethyl ] -phosphate, Aminotriazole (AT) and butylthionine sulfoximine are preferred.

The viscosity range IV (dl/g) of the sustained-release auxiliary material is 0.1-0.8, and the sustained-release auxiliary material is selected from racemic polylactic acid (D, L-PLA), racemic polylactic acid/glycollic acid copolymer (D, L-PLGA), monomethyl polyethylene glycol/polylactic acid (MPEG-PLA), monomethyl polyethylene glycol/polylactic acid copolymer (MPEG-PLGA), polyethylene glycol/polylactic acid (PLA-PEG-PLA), polyethylene glycol/polylactic acid copolymer (PLGA-PEG-PLGA), carboxyl-terminated polylactic acid (PLA-COOH), carboxyl-terminated polylactic acid/glycollic acid copolymer (PLGA-COOH), polifeprosan, difatty fatty acid and sebacic acid copolymer (PFAD-SA), poly (erucic acid dimer-sebacic acid) [ P (EAD-SA) ], poly (fumaric acid-sebacic acid) [ P (FA-SA) ], poly (FA-sebacic acid) ], and the like, Ethylene vinyl acetate copolymer (EVAc), polylactic acid (PLA), polyglycolic acid and glycolic acid copolymer (PLGA), Polydioxanone (PDO), polytrimethylene carbonate (PTMC), xylitol, oligosaccharide, chondroitin, chitin, chitosan, hyaluronic acid, collagen, gelatin, poloxamer, albumin glue or their combination; the suspending agent is selected from one or more of sodium carboxymethylcellulose, (iodine) glycerol, dimethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, Tween 20, Tween 40 and Tween 80.

The medicinal auxiliary materials are more than hundreds of medicinal auxiliary materials with slow release effect, particularly, the platinum compounds selected in the invention can be slowly released in human bodies or animal bodies within a certain time period, which is not obvious, and the selection of the specific slow release auxiliary materials and the slow release medicines can be determined only by a great deal of creative labor. Too slow release to achieve effective drug concentration and thus ineffective killing of tumor cells; if the release is too fast, a burst will be caused, which is likely to cause systemic toxicity like conventional injections. The related data, particularly the data of the release characteristics in animals, can be obtained through a large number of creative experiments in vivo and in vitro, can not be determined through limited experiments, and is non-obvious.

The compositions of the invention may be prepared in a manner known per se, for example, by means of conventional mixing, dissolving, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. The carrier includes various excipients and adjuvants. Suitable formulations may be prepared according to the chosen route of administration. Such as injection, oral administration, inhalation, suppository, patch, implant, etc. For transmucosal and transdermal administration, the use of penetrants appropriate to the permeation barrier in the formulation is generally known in the art.

Can be made into oral preparation in the form of tablet, pill, disintegrating agent, dragee, capsule, push-fit capsule, soft capsule, liquid, gel, syrup, slurry, suspension, etc.

Among the various formulations, long acting formulations are preferred, with topical application of long acting formulations being most preferred. The latter can be applied locally to the tumor by implantation (rectal, transmucosal, transdermal, enteral, intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections), with significantly reduced systemic toxicity while effectively achieving and maintaining local drug concentrations.

Administration is by topical means, e.g., by direct injection into a particular tissue, usually in the form of a depot or sustained release formulation.

Thus, the main form of the present invention is a sustained release agent including a sustained release implant and a sustained release injection.

The main form of the invention is a sustained-release injection, which consists of sustained-release microspheres and a solvent. Specifically, the anticancer sustained-release injection consists of the following components:

(A) a sustained release microsphere comprising:

0.01-60% of anticancer active ingredient

Sustained release excipients 4099.99%

0.0 to 30 percent of suspending agent

The above are weight percentages

And

(B) the solvent is common solvent or special solvent containing suspending agent.

Wherein,

the effective anticancer components are PI3K inhibitor, pyrimidine analogue and/or DNA repair enzyme inhibitor and glucocorticoid;

the slow release auxiliary material is selected from one or the combination of the following materials:

a) polylactic acid;

b) copolymers of polyglycolic acid and glycolic acid;

c) polifeprosan;

d) polifeprosan in combination with polylactic acid or a copolymer of glycolic acid and glycolic acid;

e) a di-fatty acid and sebacic acid copolymer;

f) poly (erucic acid dimer-sebacic acid) copolymer;

g) poly (fumaric acid-sebacic acid) copolymer.

The suspending agent is selected from one or more of sodium carboxymethylcellulose, iodine glycerol, dimethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, Tween 20, Tween 40 and Tween 80,

the viscosity of the suspending agent is 100cp-3000cp (at 20 ℃ -30 ℃).

The anticancer active ingredient in the sustained-release injection microsphere is a combination of glucocorticoid with effective anticancer amount and chemotherapeutic drugs selected from phosphoinositide 3-kinase (PI3K) inhibitor, pyrimidine analogue and/or DNA repair enzyme inhibitor.

The anticancer active ingredients in the anticancer sustained-release injection microsphere are preferably as follows:

(1) (ii) combinations of 0.1-10% prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone or triamcinolone acetonide with 1-40% 7-hydroxy-astrosporin, 7-O-alkyl-astrosporin, β -methoxystaurosporin, alkyl phosphocholine or hexadecyl phosphocholine;

(2)0.1 to 10 percent of prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone or triamcinolone acetonide, 1 to 40 percent of O4-benzyl folic acid, 2, 4, 5-triamino-6-benzyloxy pyrimidine, a combination of 2, 4-diamino-6-benzyloxy-5-nitrosopyrimidine, 2, 4-diamino-6-benzyloxy-5-bromopyrimidine, 2-amino-4-benzyloxy-5-nitropyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitropyrimidine, 2, 4-diamino-6-benzyloxy-s-triazine, or 2-amino-O4-benzylpteridine; or

(3) 0.1-10% prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone or triamcinolone acetonide, and 1-40% imidazopiperazine, imidazopyridine, wortmannin, benzopyran, 6-aryl-2-morphinol-4-yl-pyran-4-yl, 2- (4-morpholino) -8-phenylchromone, 7-ethyl-10-hydroxycamptothecin, 3-cyano-6-hydrazonomethyl-5- (4-pyridyl) pyridine- [1H ] -2-1, phenylbutyric acid, methoxyamine, hydroxylamine, inositol polyphosphate, tetradecyl phosphorylcholine phosphate, hexakisdecyl (N-N-N-trimethyl) hexanolamine phosphate, hexakis (N-N-N-trimethyl) hexanolamine, Combinations of octadecyl phosphorylcholine, octadecyl- [2- (N-methylpiperidine) ethyl ] -phosphate, aminotriazole, or butylthionine sulfoximine.

The most preferable sustained-release auxiliary materials in the sustained-release microspheres and the weight percentage thereof are as follows:

(1) 55-95% PLA;

(2) 50-95% PLGA;

(3) 50-95% of polifeprosan;

(4) 55-95% of a copolymer of di-fatty acid and sebacic acid;

(5) a combination of polifeprosan 30-60% and PLA 30-60% or PLGA 30-60%;

(6) 40-95% of xylitol, oligosaccharide, chondroitin, chitin, hyaluronic acid, collagen, gelatin, chitosan, poloxamer or albumin glue; or

(7) 40-95% of racemic polylactic acid, racemic polylactic acid/glycollic acid copolymer, monomethyl polyethylene glycol/polylactic acid copolymer, polyethylene glycol/polylactic acid copolymer, carboxyl-terminated polylactic acid or carboxyl-terminated polylactic acid/glycollic acid copolymer.

In addition to the above-mentioned adjuvants, other substances can be selected and used as described in detail in U.S. Pat. Nos. 4757128, 4857311, 4888176 and 4789724 and "pharmaceutical adjuvants" in general (p. 123, published by Sichuan scientific and technical Press 1993, compiled by Luoming and high-tech). In addition, Chinese patent (application No. 96115937.5; 91109723.6; 9710703.3; 01803562.0) and U.S. patent No. 5,651,986) also list some pharmaceutical excipients, including fillers, solubilizers, absorption promoters, film-forming agents, gelling agents, pore-forming agents, excipients or retarders.

In order to adjust the drug release rate or change other characteristics of the present invention, the monomer component or molecular weight of the polymer can be changed, and the composition and ratio of the pharmaceutical excipients can be added or adjusted, and water-soluble low molecular compounds such as, but not limited to, various sugars or salts can be added. Wherein the sugar can be, but is not limited to, xylitol, oligosaccharide, (chondroitin sulfate), chitin, chitosan, etc., and the salt can be, but is not limited to, potassium salt, sodium salt, etc.

In the slow release injection, the drug slow release system can be prepared into microspheres, submicron spheres, micro emulsion, nanospheres, granules or spherical pellets, and then the injection is prepared after the drug slow release system is mixed with an injection solvent. The suspension type sustained-release injection is preferably selected from various sustained-release injections, the suspension type sustained-release injection is a preparation obtained by suspending a drug sustained-release system containing an anticancer component in injection, the used auxiliary materials are one or the combination of the sustained-release auxiliary materials, and the used solvent is a common solvent or a special solvent containing a suspending agent. Common solvents are, but not limited to, distilled water, water for injection, physiological saline, absolute ethanol or buffers formulated with various salts. The suspending agent is intended to effectively suspend the microspheres containing the drug, thereby facilitating injection.

The suspending agent is selected from one or more of sodium carboxymethylcellulose, (iodine) glycerol, dimethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, Tween 20, Tween 40 and Tween 80.

The content of the suspending agent in the common solvent depends on the characteristics of the suspending agent, and can be 0.1-30% according to the specific situation. Preferably, the suspending agent consists of:

A) 0.5-5% of sodium carboxymethylcellulose and 0.1-0.5% of Tween 80; or

B) 5-20% of mannitol and 0.1-0.5% of Tween 80; or (b).

C)0.5 to 5 percent of sodium carboxymethylcellulose, 5 to 20 percent of sorbitol and 0.1 to 0.5 percent of Tween 80.

The preparation of the solvent depends on the kind of the solvent, and common solvents are commercially available or self-made, such as distilled water, water for injection, physiological saline, absolute ethanol or buffers prepared from various salts, but the preparation must strictly follow the relevant standards. The special solvent should be selected from the type and composition of suspending agent, the composition, properties and required amount of the medicine suspended in the solvent, sustained release microsphere (or microcapsule), and the preparation method of injection, for example, sodium carboxymethylcellulose (1.5%) + mannitol and/or sorbitol (15%) and/or Tween-80 (0.1%) are dissolved in physiological saline to obtain corresponding solvent with viscosity of 10-650 cp (at 20-30 deg.C).

The invention discovers that the key factor influencing the suspension and/or injection of the medicament and/or the sustained-release microspheres is the viscosity of the solvent, and the higher the viscosity is, the better the suspension effect is and the stronger the injectability is. This unexpected finding constitutes one of the main exponential features of the present invention. The viscosity of the solvent depends on the viscosity of the suspending agent, and the viscosity of the suspending agent is 100cp-3000cp (at 20-30 ℃), preferably 1000cp-3000cp (at 20-30 ℃), and most preferably 1500cp-3000cp (at 20-30 ℃). The viscosity of the solvent prepared according to the condition is 10cp-650cp (at 20-30 ℃), preferably 20cp-650cp (at 20-30 ℃), and most preferably 60cp-650cp (at 20-30 ℃).

The preparation of injection has several methods, one is that the slow release particles (A) whose suspending agent is '0' are directly mixed in special solvent to obtain correspondent slow release particle injection; the other is that the slow release particles (A) of which the suspending agent is not 0 are mixed in a special solvent or a common solvent to obtain the corresponding slow release particle injection; and the other one is that the slow release particles (A) are mixed in common dissolvent, then suspending agent is added and mixed evenly, and the corresponding slow release particle injection is obtained. Besides, the sustained-release particles (A) can be mixed in special solvent to prepare corresponding suspension, then the water in the suspension is removed by methods such as vacuum drying, and then the suspension is suspended by special solvent or common solvent to obtain the corresponding sustained-release particle injection. The above methods are merely illustrative and not restrictive of the invention. It is noted that the concentration of the suspended drug or the sustained release microspheres (or microcapsules) in the injection may be, but is not limited to, 10-400mg/ml, but is preferably 30-300mg/ml, and most preferably 50-200mg/ml, depending on the particular need. The viscosity of the injection is 50-1000 cp (at 20-30 deg C), preferably 100-1000 cp (at 20-30 deg C), and most preferably 200-650 cp (at 20-30 deg C). Such a viscosity is suitable for 18-22 gauge needles and for specially made needles with larger (to 3 mm) inside diameters.

The method of preparation of the sustained release injection is arbitrary and can be prepared by several methods: such as, but not limited to, mixing, melting, dissolving, spray drying to prepare microspheres, dissolving in combination with freezing (drying) and pulverizing to form fine powders, liposome-encapsulating, and emulsifying. Among them, a dissolving method (i.e., solvent evaporation method), a drying method, a spray drying method and an emulsification method are preferable. The microspheres can be used for preparing the various sustained-release injections, and the method is arbitrary. The microspheres used may have a particle size in the range of 5-400um, preferably 10-300um, most preferably 20-200 um.

The microspheres can also be used for preparing other sustained-release injections, such as gel injections and block copolymer micelle injections. The block copolymer micelle is formed by a hydrophobic-hydrophilic block copolymer in an aqueous solution and has a spherical core-shell structure, wherein the hydrophobic block forms a core, and the hydrophilic block forms a shell. The drug-loaded micelle is injected into the body to achieve the purpose of controlling the release of the drug or targeting therapy. The drug carrier is any one of the above or the combination thereof. Of these, polyethylene glycol (PEG) having a molecular weight of 1000-15000 is preferable as the hydrophilic block of the micelle copolymer, and biodegradable polymers such as PLA, polylactide, polycaprolactone and copolymers thereof (molecular weight 1500-25000) are preferable as the hydrophobic block of the micelle copolymer. The block copolymer micelles may have a particle size in the range of 10 to 300um, preferably 20 to 200 um. The gel injection is prepared by dissolving biodegradable polymer (such as PLA, PLGA or DL-LA and epsilon-caprolactone copolymer) in certain amphiphilic solvent, adding the medicine, mixing (or suspending) with the solvent to form gel with good fluidity, and can be injected around tumor or in tumor. Once injected, the amphiphilic solvent diffuses into the body fluid quickly, and the water in the body fluid permeates into the gel, so that the polymer is solidified and the drug is released slowly.

The sustained-release microspheres can also be used for preparing sustained-release implants, the used pharmaceutical excipients can be any one or more of the above pharmaceutical excipients, but water-soluble high molecular polymers are taken as the main choice, and in various high molecular polymers, polylactic acid, sebacic acid, a mixture or copolymer of high molecular polymers containing polylactic acid or sebacic acid are taken as the first choice, and the mixture and copolymer can be selected from, but are not limited to, PLA, PLGA, a mixture of PLA and PLGA, and a mixture or copolymer of sebacic acid and aromatic polyanhydride or aliphatic polyanhydride. The blending ratio of polylactic acid (PLA) to polyglycolic acid is 10/90 to 90/10 (by weight), preferably 25/75 to 75/25 (by weight). The method of blending is arbitrary. The contents of glycolic acid and lactic acid in copolymerization are respectively 10-90% and 90-10% by weight. The aromatic polyanhydride is represented by p-carboxyphenylpropane (p-CPP), the content of the p-carboxyphenylpropane (p-CPP) and sebacic acid in copolymerization is respectively 10-60% and 20-90% by weight, and the blending weight ratio is 10-40: 50-90, preferably 15-30: 65-85.

Still another form of the anticancer drug sustained-release preparation of the present invention is that the anticancer drug sustained-release preparation is a sustained-release implant. The effective components of the anticancer implant can be uniformly packaged in the whole pharmaceutic adjuvant, and also can be packaged in the center of a carrier support or on the surface of the carrier support; the active principle can be released by direct diffusion and/or by degradation via polymers.

The slow release implant is characterized in that the slow release auxiliary material contains any one or more of the other auxiliary materials besides the high molecular polymer. The added pharmaceutic adjuvants are collectively called as additives. The additives can be classified into fillers, pore-forming agents, excipients, dispersants, isotonic agents, preservatives, retarding agents, solubilizers, absorption enhancers, film-forming agents, gelling agents, etc. according to their functions.

The main components of the sustained-release implant can be prepared into various dosage forms. Such as, but not limited to, capsules, sustained release formulations, implants, sustained release implants, and the like; in various shapes such as, but not limited to, granules, pills, tablets, powders, spheres, chunks, needles, rods, columns, and films. Among various dosage forms, slow release implants in vivo are preferred. The size of the volume depends on the location and size of the lesion. It can be in the form of rod of 0.1-5mm (thick) × 1-10mm (long), or in the form of sheet.

The optimal dosage form of the sustained-release implant is biocompatible, degradable and absorbable sustained-release implant, and can be prepared into various shapes and various dosage forms according to different clinical requirements. The packaging method and procedure for its main ingredients are described in detail in US patent (US5651986) and include several methods for preparing sustained release formulations: such as, but not limited to, (i) mixing a carrier support powder with a drug and then compressing into an implant, a so-called mixing process; (ii) melting the carrier support, mixing with the drug to be packaged, and then cooling the solid, the so-called melt process; (iii) dissolving the carrier support in a solvent, dissolving or dispersing the drug to be packaged in a polymer solution, and then evaporating the solvent and drying, the so-called dissolution method; (iv) spray drying; and (v) freeze-drying method.

The sustained-release auxiliary materials and the weight percentage thereof in the sustained-release implant can refer to the sustained-release injection.

The route of administration depends on a variety of factors, and in order to achieve effective concentrations at the site of the primary or metastatic tumor, the drug may be administered by a variety of routes, such as subcutaneous, intraluminal (e.g., intraperitoneal, thoracic, and intravertebral), intratumoral, peritumoral injection or placement, selective arterial injection, intralymph node, and intramedulary injection. Selective arterial injection, intracavitary, intratumoral, peritumoral injection or placement is preferred.

The invention can be used for preparing pharmaceutical preparations for treating various tumors of human and animals, mainly sustained-release injections or sustained-release implants, wherein the tumors comprise primary or metastatic cancers or sarcomas or carcinosarcomas originated from brain, central nervous system, kidney, liver, gall bladder, head and neck, oral cavity, thyroid, skin, mucous membrane, gland, blood vessel, bone tissue, lymph node, lung, esophagus, stomach, mammary gland, pancreas, eye, nasopharynx, uterus, ovary, endometrium, cervix, prostate, bladder, colon and rectum.

The application and the synergy mode of the sustained-release implant are the same as those of an anticancer sustained-release injection, namely the combination of a locally-placed chemotherapy synergist and an anticancer medicament administrated by other routes, the combination of a locally-placed anticancer medicament and a chemotherapy synergist administrated by other routes, and the combination of a locally-placed anticancer medicament and a locally-placed chemotherapy synergist. Wherein the locally applied anticancer drug and the chemotherapeutic synergist can be produced, packaged, sold and used separately or jointly. The package refers to the loading process of the drug for the auxiliary materials and the internal and external package of the drug-containing sustained release agent for transportation and/or storage. Drug loading processes include, but are not limited to, weighing, dissolving, mixing, drying, shaping, coating, spraying, granulating, and the like.

The clinically applicable dose of the anticancer agent depends on the patient's condition and may be from 0.001 to 300mg/kg body weight, preferably 0.01 to 200mg/kg, most preferably 1 to 100 mg/kg. And the hormone is used in an amount of only one percent to one tenth of the amount.

The sustained-release injection or the sustained-release implant prepared by the invention can also be added with other medicinal components, such as, but not limited to, antibiotics, analgesic drugs, anticoagulant drugs, hemostatic drugs and the like.

The technical process of the invention is further described by the following tests and examples:

test 1 comparison of local drug concentrations after different modes of glucocorticoid application

Using white rat as test object, 2X 10⁵Injecting the prostate tumor cells subcutaneously into the quaternary costal region to treat the tumorGrow to 1 cm diameter and group them. Each group was 5mg/kg glucocorticoid (dexamethasone). The results of measuring the content (%) of the medicament in the tumor at different times show that the local medicament concentration difference of the glucocorticoid applied in different modes is obvious, the effective medicament concentration of the part where the tumor is located can be obviously improved and effectively maintained by local administration, and the effect of placing the sustained-release implant in the tumor and injecting the sustained-release injection in the tumor is the best. However, the intratumoral injection of the sustained-release injection is most convenient and easy to operate. This finding constitutes an important feature of the present invention. This is further confirmed by the following relevant tumor inhibition test.

Experiment 2 comparison of in vivo tumor inhibition after different glucocorticoid application

Using white rat as test object, 2X 10⁵Individual breast tumor cells were injected subcutaneously into the quaternary costal region and grouped after tumors grew to 0.5 cm diameter. Each group dose was 1.5mg/kg glucocorticoid (betamethasone). The volume of the tumor was measured on the 10 th day after the treatment, and the treatment effect was compared. The results show that the glucocorticoid has obvious difference in tumor inhibition effect after being applied in different modes, and the local administration can obviously improve and effectively maintain the effective drug concentration of the tumor part, wherein the effect of placing the sustained-release implant in the tumor and injecting the sustained-release injection in the tumor is the best. However, the intratumoral injection of the sustained-release injection is most convenient and easy to operate. Not only has good curative effect, but also has little toxic and side effect.

Experiment 3 in vivo tumor suppression Effect of glucocorticoid-containing and anticancer drug (sustained Release injection)

Using white rat as test object, 2X 10⁵Individual pancreatic tumor cells were injected subcutaneously into the quaternary costal region and were divided into the following 10 groups 14 days after tumor growth (see table 1). The first group was the control, and groups 2 to 10 were the treatment groups, all of which were intratumorally injected. The dosage of the angiogenesis inhibitor is 2.5mg/kg, and the dosage of the anti-cancer drug is 7.5 mg/kg. Tumor volume was measured on day 21 after treatment and the treatment effect was compared (see table 1).

TABLE 1

Test set (n)	Is treated by	Tumor volume (cm)³)	P value
Test set (n)	Is treated by	Tumor volume (cm)³)	P value	1(6)	Control	64±10
2(6)	Glucocorticoids	50±8.0	＜0.05	1(6)	Control	64±10
2(6)	Glucocorticoids	50±8.0	＜0.05	3(6)	UCN-01	44±6.2	＜0.01
4(6)	UCN-02	32±7.4	＜0.01	3(6)	UCN-01	44±6.2	＜0.01
4(6)	UCN-02	32±7.4	＜0.01	5(6)	MIL	44±8.0	＜0.01
6(6)	D-21266	42±6.0	＜0.01	5(6)	MIL	44±8.0	＜0.01
6(6)	D-21266	42±6.0	＜0.01	7(6)	Glucocorticoid + UCN-01	20±4.2	＜0.001
8(6)	Glucocorticoid + UCN-02	30±5.4	＜0.001	7(6)	Glucocorticoid + UCN-01	20±4.2	＜0.001
8(6)	Glucocorticoid + UCN-02	30±5.4	＜0.001	9(6)	Glucocorticoid + MIL	22±4.2	＜0.001
10(6)	Glucocorticoid + D-21266	18±4.0	＜0.001	9(6)	Glucocorticoid + MIL	22±4.2	＜0.001

The results show that glucocorticoid (betamethasone) and the used anticancer drug, phosphoinositide 3-kinase (PI3K) inhibitor (wherein UCN-01: 7-hydroxyl-astrosporin, UCN-02: 7-O-alkyl-astrosporin, MIL: Miltefosine, D-21266: octadecyl- (1, 1-dimethyl-4-piperidine) phosphate or perifosine) have obvious inhibition effect on the growth of various tumor cells when being used independently at the concentration, and can show obvious synergistic effect when being used in combination

Test 4 antitumor Effect of glucocorticoid and anticancer drug (sustained Release injection)

The tumor cells include CNS-1, C6, 9L, gastric gland epithelial cancer (SA), bone tumor (BC), breast cancer (BA), lung cancer (LH), papillary thyroid adenocarcinoma (PAT), and liver cancer. The medicine is injected intratumorally. Therapeutic efficacy (see table 2). The dosage of glucocorticoid is 2.5mg/kg, and the dosage of anticancer drugs is 10 mg/kg. The size of tumor volume was measured on day 20 after the treatment, and the treatment effect was compared using the tumor growth inhibition (%) as an index (see table 2).

TABLE 2

Tumor cell	Glucocorticoids	04-BA	UCN-01	UCN-02	Glucocorticoid +04-BA	Glucocorticoid + UCN-1	Glucocorticoid + UCN-2
Tumor cell	Glucocorticoids	04-BA	UCN-01	UCN-02	Glucocorticoid +04-BA	Glucocorticoid + UCN-1	Glucocorticoid + UCN-2	CNS	36％	42％	42％	40％	76％	74％	78％
C6	34％	44％	30％	64％	74％	80％	80％	CNS	36％	42％	42％	40％	76％	74％	78％
C6	34％	44％	30％	64％	74％	80％	80％	SA	28％	50％	50％	52％	86％	72％	72％
BC	38％	42％	54％	46％	74％	82％	82％	SA	28％	50％	50％	52％	86％	72％	72％
BC	38％	42％	54％	46％	74％	82％	82％	BA	28％	60％	42％	60％	82％	72％	72％
LH	42％	56％	2％	48％	90％	86％	80％	BA	28％	60％	42％	60％	82％	72％	72％
LH	42％	56％	2％	48％	90％	86％	80％	PAT	38％	42％	46％	50％	80％	84％	78％

The results show that the glucocorticoid (prednisolone) and the anticancer drug (O4-BA: O4-benzyluric acid; UCN-01: 7-hydroxyl-astrosporin; UCN-02: 7-O-alkyl-astrosporin) have obvious inhibition effect on the growth of various tumor cells when being applied independently at the concentration, and can show obvious synergistic effect when being applied jointly.

Test 5 antitumor Effect of glucocorticoid and anticancer drug (sustained Release injection)

Using white rat as test pairElephant, 2 x 10⁵Individual liver tumor cells were injected subcutaneously into the quaternary costal region and were divided into the following 10 groups 14 days after tumor growth (see table 3). The first group was the control, and groups 2 to 10 were the treatment groups, with the sustained release implant placed intratumorally. The dosage of glucocorticoid is 5mg/kg, and the dosage of anticancer drug is 10 mg/kg. The size of tumor volume was measured on day 20 after the treatment, and the treatment effect was compared using the tumor growth inhibition (%) as an index (see table 3).

TABLE 3

Test set (n)	Is treated by	Tumor volume (cm)³)	P value
Test set (n)	Is treated by	Tumor volume (cm)³)	P value	1(6)	Control	60±12
2(6)	ilmofosine	48±5.0	＜0.05	1(6)	Control	60±12
2(6)	ilmofosine	48±5.0	＜0.05	3(6)	Glucocorticoids	44±2.2	＜0.01
4(6)	ilmofosine + glucocorticosteroid	32±2.6	＜0.001	3(6)	Glucocorticoids	44±2.2	＜0.01
4(6)	ilmofosine + glucocorticosteroid	32±2.6	＜0.001	5(6)	AMG-PC	46±3.2	＜0.01
6(6)	AMG-PC + glucocorticoids	22±3.0	＜0.001	5(6)	AMG-PC	46±3.2	＜0.01
6(6)	AMG-PC + glucocorticoids	22±3.0	＜0.001	7(6)	edelfosine	30±2.6	＜0.01
8(6)	Edelfosine + glucocorticoids	20±2.4	＜0.001	7(6)	edelfosine	30±2.6	＜0.01
8(6)	Edelfosine + glucocorticoids	20±2.4	＜0.001	9(6)	IDOU	32±3.4	＜0.01
10(6)	IDOU + glucocorticoids	16±2.2	＜0.001	9(6)	IDOU	32±3.4	＜0.01

The results show that the glucocorticoid (hyaluronidase) and the anti-cancer drug-PI 3K inhibitor (AMG-PC: 1-O-hexadecyl-2-O-methyl-rac-propanetriyl-3-phosphorylcholine; edelfosine: 1-O-octadecyl-2-O-methyl-rac-propanetriyl-3-phosphorylcholine; ilmofosine: 1-O-octadecyl-2-O-methyl-sn-propanetriyl-3-phosphorylcholine; IDOU: 5-iodo-2' -deoxyguanosine) used in the concentrations have obvious inhibition effects on the growth of various tumor cells when being used alone, and can show obvious synergistic effects when being used in combination.

Test 6 antitumor Effect of glucocorticoid and anticancer drug (sustained Release injection)

Using white rat as test object, 2X 10⁵One prostate tumor cell was injected subcutaneously into the quaternary rib area and 14 days after tumor growth was divided into negative control (blank), single drug treatment group (glucocorticoid or anticancer drug) and combination treatment group (glucocorticoid and anticancer drug). Glucocorticoid (2mg/kg) is injected intratumorally, and anticancer drug (18mg/kg) is injected intraperitoneally. Tumor volume was measured on day 20 after treatment, and the therapeutic effect was compared using tumor growth inhibition as an index (see table 4).

TABLE 4

Test set (n)	Is treated by	Tumor inhibition ratio (%)	P value
Test set (n)	Is treated by	Tumor inhibition ratio (%)	P value	1(6)	Control	-
2(6)	Glucocorticoids	38	＜0.05	1(6)	Control	-
2(6)	Glucocorticoids	38	＜0.05	3(6)	Imidazopiperazines	28	＜0.01
4(6)	Imidazopyridines as inhibitors of HIV	30	＜0.01	3(6)	Imidazopiperazines	28	＜0.01
4(6)	Imidazopyridines as inhibitors of HIV	30	＜0.01	5(6)	Wortmannin	32	＜0.01
6(6)	Benzopyrans	32	＜0.01	5(6)	Wortmannin	32	＜0.01
6(6)	Benzopyrans	32	＜0.01	7(6)	Glucocorticoid + imidazopiperazines	62	＜0.001
8(6)	Glucocorticoid + imidazopyridine	70	＜0.001	7(6)	Glucocorticoid + imidazopiperazines	62	＜0.001
8(6)	Glucocorticoid + imidazopyridine	70	＜0.001	9(6)	Glucocorticoid + wortmannin	66	＜0.001
10(6)	Glucocorticoid + benzopyran	72	＜0.001	9(6)	Glucocorticoid + wortmannin	66	＜0.001

The results show that the glucocorticoid (methylprednisolone) and the anti-cancer drug-DNA-dependent protein kinase inhibitor (wherein, the imidazopiperazine, the imidazopyridine, the wortmannin and the benzopyran) have obvious inhibition effects on the growth of various tumor cells when being used independently at the concentration, and can show obvious synergistic effects when being used in combination.

Test 7 antitumor Effect of glucocorticoid and anticancer drug (sustained Release injection)

Using white rat as test object, 2X 10⁵Each breast tumor cell was injected subcutaneously into the costal region of the patient, and the tumor was divided into a negative control (blank), a single drug treatment group, and a combination treatment group 14 days after the tumor had grown. Glucocorticoid (12mg/kg) was injected intraperitoneally, and anticancer drug (2mg/kg) was injected peritumorally. Tumor volume was measured on day 21 after treatment, and the therapeutic effect was compared using tumor growth inhibition as an index (see table 5).

TABLE 5

Test set (n)	Is treated by	Tumor inhibition ratio (%)	P value
Test set (n)	Is treated by	Tumor inhibition ratio (%)	P value	1(6)	Control	-
2(6)	Glucocorticoids	32	＜0.05	1(6)	Control	-
2(6)	Glucocorticoids	32	＜0.05	3(6)	LY294002	40	＜0.01
4(6)	SU11752	32	＜0.01	3(6)	LY294002	40	＜0.01
4(6)	SU11752	32	＜0.01	5(6)	SN-38	42	＜0.01
6(6)	OK-1035	40	＜0.01	5(6)	SN-38	42	＜0.01
6(6)	OK-1035	40	＜0.01	7(6)	Glucocorticoid + LY294002	66	＜0.001
8(6)	Glucocorticoid + SU11752	76	＜0.001	7(6)	Glucocorticoid + LY294002	66	＜0.001
8(6)	Glucocorticoid + SU11752	76	＜0.001	9(6)	Glucocorticoid + SN-38	70	＜0.001
10(6)	Glucocorticoid + OK-1035	72	＜0.001	9(6)	Glucocorticoid + SN-38	70	＜0.001

The results show that the glucocorticoid (triamcinolone) and the anti-cancer drug-DNA-dependent protein kinase inhibitor (wherein, LY 294002: 2- (4-morpholino) -8-phenylchromone; SU 11752: kinase inhibitor; SN-38: 7-ethyl-10-hydroxycamptothecin; OK-1035: 3-cyano-6-hydrazonomethyl-5- (4-pyridyl) pyridine- [1H ] -2-1) have obvious inhibition effect on the growth of a plurality of tumor cells when being used independently at the concentration, and can show obvious synergistic effect when being used in combination.

Test 8 antitumor Effect of glucocorticoid and anticancer drug (sustained Release implant)

Using white rat as test object, 2X 10⁵Each breast tumor cell was injected subcutaneously into the costal region of the patient, and the tumor was divided into a negative control (blank), a single drug treatment group, and a combination treatment group 14 days after the tumor had grown. The slow release implant is placed in the tumor. Glucocorticoid (5mg/kg) was injected intraperitoneally, and anticancer drug (10mg/kg) was injected peritumorally. Tumor volume was measured on day 21 after treatment, and the therapeutic effect was compared using tumor growth inhibition as an index (see table 6).

TABLE 6

Test set (n)	Is treated by	Tumor inhibition ratio (%)	P value
Test set (n)	Is treated by	Tumor inhibition ratio (%)	P value	1(6)	Control	-
2(6)	Glucocorticoids	40	＜0.05	1(6)	Control	-
2(6)	Glucocorticoids	40	＜0.05	3(6)	Methoxyamine	30	＜0.05
4(6)	Minocycline	32	＜0.05	3(6)	Methoxyamine	30	＜0.05
4(6)	Minocycline	32	＜0.05	5(6)	Hydroxy amines	34	＜0.05
6(6)	O-methylhydroxylamine	36	＜0.01	5(6)	Hydroxy amines	34	＜0.05
6(6)	O-methylhydroxylamine	36	＜0.01	7(6)	Glucocorticoid + methoxyamine	80	＜0.01
8(6)	Glucocorticoid + minocycline	76	＜0.01	7(6)	Glucocorticoid + methoxyamine	80	＜0.01
8(6)	Glucocorticoid + minocycline	76	＜0.01	9(6)	Glucocorticoid + hydroxylamine	74	＜0.01
10(6)	Glucocorticoid + O-methylhydroxylamine	78	＜0.001	9(6)	Glucocorticoid + hydroxylamine	74	＜0.01

The results show that the glucocorticoid (triamcinolone acetonide) and the anti-cancer drug-DNA-dependent protein kinase inhibitor have obvious inhibition effect on the growth of a plurality of tumor cells when being singly applied at the concentration, and can show obvious synergistic effect when being jointly applied.

Test 9 antitumor Effect of glucocorticoid and anticancer drug (sustained Release implant)

The tumor-inhibiting effects of glucocorticoids and anticancer drugs (sustained release implants) were determined as described in test 8, and the tumor growth inhibition rates are shown in Table 7.

TABLE 7

Test set (n)	Is treated by	Tumor inhibition ratio (%)	P value
Test set (n)	Is treated by	Tumor inhibition ratio (%)	P value	1(6)	Control	-
2(6)	Glucocorticoids	42	＜0.05	1(6)	Control	-
2(6)	Glucocorticoids	42	＜0.05	3(6)	3-AB	42	＜0.01
4(6)	Benzamide derivatives	36	＜0.01	3(6)	3-AB	42	＜0.01
4(6)	Benzamide derivatives	36	＜0.01	5(6)	PD128763	34	＜0.01
6(6)	AG14361	26	＜0.01	5(6)	PD128763	34	＜0.01
6(6)	AG14361	26	＜0.01	7(6)	Glucocorticoid +3-AB	70	＜0.001
8(6)	Glucocorticoid + benzamide	78	＜0.001	7(6)	Glucocorticoid +3-AB	70	＜0.001
8(6)	Glucocorticoid + benzamide	78	＜0.001	9(6)	Glucocorticoid + PD128763	74	＜0.001
10(6)	Glucocorticoid + AG14361	82	＜0.001	9(6)	Glucocorticoid + PD128763	74	＜0.001

The results show that the glucocorticoid (dexamethasone) and the anti-cancer drug, namely a poly (ADP-ribose) polymerase inhibitor (wherein, 3-AB: 3-aminobenzamide; benzamide; PD 128763: 3, 4-dihydromethoxyisoquinoline-1 (2H) benzamide; AG 14361: polymerase inhibitor) have obvious inhibition effect on the growth of a plurality of tumor cells when being singly applied at the concentration, and can show obvious synergistic effect when being combined for application.

Test 10 antitumor Effect of glucocorticoid and anticancer drug (sustained Release injection)

The tumor-inhibiting effects of glucocorticoids and anticancer drugs (sustained release implants) were determined as described in test 8, and the tumor growth inhibition rates are shown in Table 8.

TABLE 8

Test set (n)	Is treated by	Tumor inhibition ratio (%)	P value
Test set (n)	Is treated by	Tumor inhibition ratio (%)	P value	1(6)	Control	-
2(6)	Glucocorticoids	46	＜0.05	1(6)	Control	-
2(6)	Glucocorticoids	46	＜0.05	3(6)	BZ1-6	50	＜0.01
4(6)	TI1-5	30	＜0.01	3(6)	BZ1-6	50	＜0.01
4(6)	TI1-5	30	＜0.01	5(6)	TBC	36	＜0.01
6(6)	Benzimidazole compounds	42	＜0.01	5(6)	TBC	36	＜0.01
6(6)	Benzimidazole compounds	42	＜0.01	7(6)	Glucocorticoid + BZ1-6	78	＜0.001
8(6)	Glucocorticoid + TI1-5	80	＜0.001	7(6)	Glucocorticoid + BZ1-6	78	＜0.001
8(6)	Glucocorticoid + TI1-5	80	＜0.001	9(6)	Glucocorticoid + TBC	72	＜0.001
10(6)	Glucocorticoid + benzimidazole	80	＜0.001	9(6)	Glucocorticoid + TBC	72	＜0.001

The results show that the glucocorticoid (dexamethasone and betamethasone are respectively 2.5mg/kg) and the anti-cancer drug-poly (ADP-ribose) polymerase inhibitor (wherein, BZ 1-6: benzimidazole-4-carboxamide; TI 1-5: tricyclic lactam hydrogen sulfide; TBC: tricyclic benzimidazole carboxamide, benzimidazole) have obvious inhibition effect on the growth of a plurality of tumor cells when being used independently at the concentration, and can show obvious synergistic effect when being used in combination.

Test 11 antitumor Effect of glucocorticoid and/or anticancer drug (sustained Release implant)

The tumor-inhibiting effect of glucocorticoids and/or anticancer drugs (sustained release implants) was determined as described in test 8, and the tumor growth inhibition rate is shown in Table 9.

TABLE 9

Test set (n)	Is treated by	Percent inhibition of swelling (%)	P value
Test set (n)	Is treated by	Percent inhibition of swelling (%)	P value	1(6)	Control	-
2(6)	Glucocorticoids	36	＜0.05	1(6)	Control	-
2(6)	Glucocorticoids	36	＜0.05	3(6)	NU1025	36	＜0.01
4(6)	PBC	40	＜0.01	3(6)	NU1025	36	＜0.01
4(6)	PBC	40	＜0.01	5(6)	MPBC	48	＜0.01
6(6)	NU1085	58	＜0.01	5(6)	MPBC	48	＜0.01
6(6)	NU1085	58	＜0.01	7(6)	Glucocorticoid + NU1025	80	＜0.001
8(6)	Glucocorticoid + PBC	76	＜0.001	7(6)	Glucocorticoid + NU1025	80	＜0.001
8(6)	Glucocorticoid + PBC	76	＜0.001	9(6)	Glucocorticoid + MPBC	80	＜0.001
10(6)	Glucocorticoid + NU1085	88	＜0.001	9(6)	Glucocorticoid + MPBC	80	＜0.001

The above results show that the glucocorticoid (betamethasone 2.5mg/kg) and the anticancer drug poly (ADP-ribose) polymerase inhibitor (PBC: 2-phenyl-1H-benzimidazole-4-carboxamide; MPBC: 2- (3-methoxyphenyl) -1H-benzimidazole-4-carboxamide (2- (3-methoxyphenyl) -1H-benzimidazole-4-carboxamide); NU 1025: 8-hydroxy-2-methylquinazolinone; NU 1085: 2- (4-hydroxyphenyl) benzimidazole-4-carboxamide) used in the above concentrations all have significant inhibitory effects on the growth of various tumor cells, and when used in combination, have significant synergistic effects.

Test 12 antitumor Effect of glucocorticoid and/or anticancer drug (sustained Release implant)

The tumor-inhibiting effect of glucocorticoids and/or anticancer drugs (sustained-release implants) was measured as described in test 6, and the tumor growth inhibition rate is shown in Table 10.

Watch 10

Test set (n)	Is treated by	Tumor inhibition ratio (%)	P value
Test set (n)	Is treated by	Tumor inhibition ratio (%)	P value	1(6)	Control	-
2(6)	Glucocorticoids	40	＜0.05	1(6)	Control	-
2(6)	Glucocorticoids	40	＜0.05	3(6)	BSO	46	＜0.01
4(6)	Amino triazoles	36	＜0.01	3(6)	BSO	46	＜0.01
4(6)	Amino triazoles	36	＜0.01	5(6)	Lasiosphaeric acid	42	＜0.01
6(6)	Podophyllotoxin	30	＜0.01	5(6)	Lasiosphaeric acid	42	＜0.01
6(6)	Podophyllotoxin	30	＜0.01	7(6)	Glucocorticoid + BSO	70	＜0.001
8(6)	Glucocorticoid + aminotriazole	84	＜0.001	7(6)	Glucocorticoid + BSO	70	＜0.001
8(6)	Glucocorticoid + aminotriazole	84	＜0.001	9(6)	Glucocorticoid + puffball acid	84	＜0.001
10(6)	Glucocorticoid + neopodophyllotoxin	78	＜0.001	9(6)	Glucocorticoid + puffball acid	84	＜0.001

The results show that the used sugar reverse hormone (dexamethasone and betamethasone each 1.0mg/kg) and the anticancer approximant-poly (ADP-ribose) polymerase inhibitor (wherein BSO is butylthionine sulfoximine) have obvious inhibition effect on the growth of various tumor cells when being singly applied at the concentration, and can show obvious synergistic effect when being applied in combination.

Experiment 13 comparison of in vivo Release of glucocorticoid sustained Release implants made of polylactic acid of different molecular weights

Rats were used as test subjects and divided into groups (3/group) and subcutaneously administered equivalent amounts of glucocorticoid (dexamethasone) sustained release implants loaded with polylactic acid (PLA) of different Molecular Weights (MW). Then, the remaining amount of the drug in the implant was measured on days 1, 3, 7, 14, 21, 28 and 35, respectively, to obtain the in vivo release rate (%). The results show that the release with molecular weight 20000 is: 1 day (12%), 3 (26%), 7 (56%), 14 (80%), 21 (86%), 28 (92%) and 35 (94%). Comparing in vivo release of sustained-release implants made of polylactic acids of different molecular weights, it was found that the release was slowed down with increasing molecular weight, and as an example at day 7, the tumor suppression rate was increased with increasing molecular weight of polylactic acids, in the order of 68% (MW: 5000), 62% (MW: 15000), 54% (MW: 25000), 52% (MW: 40000) and 46 (MW: 60000), as compared with the systemic administration group.

The same result is also seen in the slow release preparation containing glucocorticoid and anticancer medicine prepared by using polylactic acid as an auxiliary material.

Particularly, the sustained-release preparation, particularly the sustained-release injection, has simple and convenient operation and good repeatability. Not only has good curative effect, but also has little toxic and side effect.

Different drug packages have different drug release characteristics from different biodegradable polymers. Further research finds that the slow-release auxiliary materials most suitable for the slow release of the medicament are one of or a combination of racemic polylactic acid, racemic polylactic acid/glycolic acid copolymer, monomethyl polyethylene glycol/polylactic acid copolymer, polyethylene glycol/polylactic acid copolymer, terminal carboxyl polylactic acid/glycolic acid copolymer, polifeprosan, di-fatty acid and sebacic acid copolymer, poly (erucic aciddipolymer-sebacic acid), poly (fumaric acid-sebacic acid), polylactic acid, polyglycolic acid and glycolic acid copolymer, xylitol, oligosaccharide, chondroitin, chitosan, hyaluronic acid, collagen, gelatin, poloxamer and albumin glue; the most suitable suspending agent is one or more of methylcellulose, hydroxymethyl cellulose, sodium carboxymethylcellulose, (iodine) glycerol, dimethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, Tween 20, Tween 40, Tween 80, or their combination.

In conclusion, the glucocorticoid and various anti-cancer drugs have obvious inhibition effect on the growth of a plurality of tumor cells when being applied independently, and can show obvious synergistic effect when being applied together. Therefore, the active ingredient of the invention is the combination of the glucocorticoid and any one (or more than one) anticancer drugs. The medicine containing the above effective components can be made into sustained release microsphere, and further made into sustained release injection and implant, wherein suspension injection formed by combining with special solvent containing suspending agent is preferred.

The sustained-release injection or sustained-release implant can be further explained by the following embodiments. The above examples and the following examples are only for further illustration of the present invention and are not intended to limit the contents and uses thereof in any way.

(IV) detailed description of the preferred embodiments

Example 1.

80 parts of polifeprosan (p-carboxyphenylpropane (p-CPP): Sebacic Acid (SA) is 20: 80) copolymer is put into a container, 100 ml of dichloromethane is added, after the mixture is dissolved and mixed evenly, 10 parts of dexamethasone and 10 parts of 7-hydroxyl-astrosporin are added, after the mixture is shaken again, the microspheres for injection containing 10 percent of dexamethasone and 10 percent of 7-hydroxyl-astrosporin are prepared by a spray drying method. Then suspending the microspheres in physiological saline containing 15 percent of mannitol to prepare the corresponding suspension type sustained-release injection. The slow release injection has the release time of 30-55 days in-vitro physiological saline and the release time of about 30 days under the skin of a mouse.

Example 2.

The procedure for preparing the sustained release injection is the same as that of example 1, except that the ratio of the polifeprosan is 50: 50; the anticancer active components and the weight percentage thereof are as follows: 0.1-10% of prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone or triamcinolone acetonide in combination with 1-40% of 7-hydroxy-astrosporin, 7-O-alkyl-astrosporin, beta-methoxystaurosporine, alkyl phosphorylcholine or hexadecyl phosphorylcholine.

Example 3.

80mg of polylactic acid (PLA) with the molecular weight peak of 20000-40000 is put into a container, 100 ml of dichloromethane is added, 5mg of prednisolone and 15mg of 7-ethyl-10-hydroxycamptothecin are added after being dissolved and mixed evenly, and the organic solvent is removed by vacuum drying after shaking up again. Freeze-pulverizing the dried solid composition containing drug to obtain micropowder containing 5% prednisolone and 15% 7-ethyl-10-hydroxycamptothecin, and suspending in physiological saline containing 1.5% sodium carboxymethylcellulose to obtain suspension type sustained release injection. The slow release injection has the release time of 20-35 days in-vitro physiological saline and the release time of about 35-50 days under the skin of a mouse.

Example 4

The steps of the method for processing the sustained-release injection are the same as the example 3, but the difference is polylactic acid (PLA) with the molecular weight peak value of 10000-:

0.1-10% prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone or triamcinolone acetonide, and 1-40% imidazopiperazine, imidazopyridine, wortmannin, benzopyran, 6-aryl-2-morphinol-4-yl-pyran-4-yl, 2- (4-morpholino) -8-phenylchromone, 7-ethyl-10-hydroxycamptothecin, 3-cyano-6-hydrazonomethyl-5- (4-pyridyl) pyridine- [1H ] -2-1, phenylbutyric acid, methoxyamine, hydroxylamine, inositol polyphosphate, tetradecyl phosphorylcholine phosphate, hexakisdecyl phosphoric acid (N-N-N-trimethyl) hexanolamine, hexakis-phenylcarnitine, and their salts, Combinations of octadecyl phosphorylcholine, octadecyl- [2- (N-methylpiperidine) ethyl ] -phosphate, aminotriazole, or butylthionine sulfoximine.

Example 5.

70mg of PLGA (50: 50) with the molecular weight peak of 10000-30000 is put into a container, 100 ml of dichloromethane is added to dissolve and mix evenly, 20mg of methylprednisolone and 10mg of benzimidazole are added to shake evenly again, and the spray drying method is used to prepare the microspheres for injection containing 20% methylprednisolone and 10% benzimidazole. Then suspending the microspheres in injection containing 5-15% of sorbitol to prepare the corresponding suspension type sustained-release injection. The slow release injection has the release time of 30-35 days in-vitro physiological saline and the release time of about 30 days under the skin of a mouse.

Example 6.

The steps of the method for processing the sustained-release injection are the same as the example 5, but the difference is that PLGA is 75: 25, the peak value of molecular weight is 20000-45000, and the anticancer active ingredients are: 1-10% of prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone or triamcinolone acetonide, 1-40% of O4-benzyl folic acid, 2, 4, 5-triamino-6-benzyloxy pyrimidine, a combination of 2, 4-diamino-6-benzyloxy-5-nitrosopyrimidine, 2, 4-diamino-6-benzyloxy-5-bromopyrimidine, 2-amino-4-benzyloxy-5-nitropyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitropyrimidine, 2, 4-diamino-6-benzyloxy-s-triazine, or 2-amino-O4-benzylpteridine.

Example 7.

40mg of polifeprosan (p-carboxyphenylpropane (p-CPP): Sebacic Acid (SA) is 20: 80) and 40mg of PLGA (50: 50) with the molecular weight peak value of 10000-30000 are placed in a container, a proper amount of dichloromethane is added, after dissolving and mixing uniformly, 4mg of triamcinolone acetonide and 16mg of butylthionine sulfoximine are added, after shaking uniformly again, the microspheres for injection containing 4% of triamcinolone acetonide and 16% of butylthionine sulfoximine are prepared by a spray drying method. Then suspending the microspheres in physiological saline containing 1.5 percent of sodium carboxymethylcellulose and 0.5 percent of Tween 80 to prepare the corresponding suspension type sustained-release injection. The slow release injection has the release time of 30-35 days in-vitro physiological saline and the release time of about 30 days under the skin of a mouse.

Example 8.

The steps of the method for processing the sustained-release injection are the same as the example 7, but the difference is that the used auxiliary material is polifeprosan 40: 60, the peak value of the PLGA molecular weight is 30000-50000, 75: 25; the anticancer active ingredients are: 1-5% triamcinolone acetonide and 1-40% imidazopiperazine, imidazopyridine, wortmannin, benzopyran, 6-aryl-2-morphinan-4-yl-pyran-4-yl, 2- (4-morpholinyl) -8-phenylchromone, 7-ethyl-10-hydroxycamptothecin, 3-cyano-6-hydrazonomethyl-5- (4-pyridyl) pyridine- [1H ] -2-1, phenylbutyric acid, methoxyamine, hydroxylamine, inositol polyphosphate, tetradecyl choline phosphate, N-N-N-trimethyl hexanolamine hexakisphosphate, octadecyl choline phosphate, octadecyl- [2- (N-methyl-piperidine) ethyl ] -phosphate, Combinations of aminotriazoles or butylthioiolixime.

Example 9

30mg of polifeprosan (20: 80) and 50mg of PLA with the molecular weight peak value of 10000-30000 are put into a container, a proper amount of dichloromethane is added, after the materials are dissolved and uniformly mixed, 5mg of dexamethasone and 15mg of O4-benzylfolic acid are added, the mixture is uniformly shaken again, and then the spray drying method is used for preparing the microspheres for injection containing 5% of dexamethasone and 15% of O4-benzylfolic acid. Then suspending the microspheres in physiological saline containing 1.5 percent of sodium carboxymethylcellulose, 15 percent of sorbitol and 0.2 percent of Tween 80 to prepare the corresponding suspension type sustained-release injection. The slow release injection has the release time in vitro physiological saline of 30-35 days and the release time under the skin of a mouse of about 40 days.

Example 10

The steps of the method for processing the sustained-release injection are the same as the example 9, but the difference is that the used auxiliary material is polifeprosan 50: 50, the peak value of PLA molecular weight is 30000-50000, and the anticancer active ingredients contained in 75: 25 are: a combination of 1-10% dexamethasone or betamethasone and 10-40% O4-benzylfolate, 2, 4, 5-triamino-6-benzyloxypyrimidine, 2, 4-diamino-6-benzyloxy-5 nitrosopyrimidine, 2, 4-diamino-6-benzyloxy-5-bromopyrimidine, 2-amino-4-benzyloxy-5-nitropyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitropyrimidine, 2, 4-diamino-6-benzyloxy-s-triazine or 2-amino-O4-benzylpteridine.

Example 11

70mg of copolymer of difatty acid and sebacic acid is put into a container, 100 ml of dichloromethane is added, after dissolving and mixing evenly, 10mg of 7-hydroxyl-astrosporin and 20mg of betamethasone are added, after shaking up again, microspheres for injection containing 10% of 7-hydroxyl-astrosporin and 20% of betamethasone are prepared by a spray drying method. Then the microspheres are prepared into the corresponding sustained-release implant by a tabletting method. The slow release implant has the release time of 30-35 days in-vitro physiological saline and the release time of about 30-40 days under the skin of a mouse.

Example 12

The procedure of the method for processing the sustained release implant is the same as that of example 11, but the difference is that the used auxiliary material is poly (erucic acid dipolymer-sebacic acid) copolymer, and the anticancer active ingredients are: a combination of 1-5% betamethasone and 10% 7-hydroxy-astrosporin, 7-O-alkyl-astrosporin, beta-methoxyastrosporin, alkylphosphocholine or hexadecylphosphocholine.

Example 13

70mg of poly (fumaric acid-sebacic acid) copolymer (50: 50) with the molecular weight peak value of 20000-450000 is put into a container, 100 ml of dichloromethane is added, after the mixture is dissolved and uniformly mixed, 10mg of dexamethasone and 20mg of neopodophyllotoxin are added, the mixture is uniformly shaken again, and then the spray drying method is used for preparing the microspheres for injection containing 10% of dexamethasone and 20% of neopodophyllotoxin. Then the microspheres are prepared into the corresponding sustained-release implant by a tabletting method. The slow release implant has the release time in vitro physiological saline of 25-30 days and the release time under the skin of a mouse of about 35-50 days.

Example 14

The procedure of processing into sustained release implant is the same as in examples 11 and 13, except that the anticancer active ingredient is: 10% dexamethasone in combination with 20% aminotriazole, butylthioneoxime, puffball acid, S-hexyl glutathione, neopodophyllotoxin, hexacyclic camptothecin or tetrarylbenzamide.

Example 15

The procedure of processing into sustained release preparation is the same as that of examples 1-14, except that the sustained release excipient is one or a combination of the following:

a) polylactic acid (PLA) with the molecular weight peak value of 5000-10000, 10000-30000, 30000-60000, 60000-100000 or 100000-150000;

b) a copolymer (PLGA) of polyglycolic acid and glycolic acid with a peak molecular weight of 5000-10000, 10000-30000, 30000-60000, 60000-100000 or 100000-150000, wherein the ratio of the polyglycolic acid to the glycolic acid is 50-95: 50-50;

c) polifeprosan in combination with polylactic acid or a copolymer of glycolic acid and glycolic acid;

d) p-carboxyphenylpropane (p-CPP) to Sebacic Acid (SA) copolymer (polifeprosan) 10: 90, 20: 80, 30: 70, 40: 60, 50: 50 or 60: 40;

e) a di-fatty acid and sebacic acid copolymer;

f) poly (erucic acid dimer-sebacic acid) copolymer;

g) poly (fumaric acid-sebacic acid) copolymer;

h) xylitol, oligosaccharide, chondroitin, chitin, chitosan, potassium salt, sodium salt, hyaluronic acid, collagen, gelatin, poloxamer or albumin glue;

i) racemic polylactic acid, racemic polylactic acid/glycolic acid copolymer, monomethyl polyethylene glycol/polylactic acid copolymer, polyethylene glycol/polylactic acid copolymer, carboxyl-terminated polylactic acid or carboxyl-terminated polylactic acid/glycolic acid copolymer.

Example 16

The procedure for preparing a sustained release injection is the same as in examples 1 to 15, except that the suspending agent used is one or a combination of the following:

a) 0.5-3.0% carboxymethylcellulose (sodium);

b) 5-15% mannitol;

c) 5-15% sorbitol;

d) 0.1-1.5% of surface active substances;

e) 0.1-0.5% tween 20.

Example 17

The procedure of processing into sustained release injection is the same as in examples 11-15, except that the anticancer active ingredient is:

(1) (ii) combinations of 0.1-10% prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone or triamcinolone acetonide with 1-40% 7-hydroxy-astrosporin, 7-O-alkyl-astrosporin, β -methoxystaurosporine, alkylphosphocholine or hexadecylphosphocholine;

(3) 0.1-10% prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone or triamcinolone acetonide, and 1-40% imidazopiperazine, imidazopyridine, wortmannin, benzopyran, 6-aryl-2-morphinol-4-yl-pyran-4-yl, 2- (4-morpholino) -8-phenylchromone, 7-ethyl-10-hydroxycamptothecin, 3-cyano-6-hydrazonomethyl-5- (4-pyridyl) pyridine- [1H ] -2-1, phenylbutyric acid, methoxyamine, hydroxylamine, inositol polyphosphate, tetradecyl phosphorylcholine phosphate, hexakisdecyl phosphoric acid (N-N-N-trimethyl) hexanolamine, hexakis-phenylcarnitine, and their salts, Combinations of octadecyl phosphorylcholine, octadecyl- [2- (N-methylpiperidine) ethyl ] -phosphate, aminotriazole, or butylthionine sulfoximine.

The present invention is not to be limited in scope by the illustrated embodiments, which are intended as individual illustrations of the invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifications are, of course, intended to be within the scope of the appended claims. It should be understood, therefore, that the foregoing description focuses on certain specific embodiments of the invention and that equivalent alterations and substitutions made thereto are within the spirit and scope of the appended claims.

The above examples are intended to illustrate, but not limit, the application of the invention. The invention is disclosed and claimed.

Claims

1. An anticancer sustained release agent carrying glucocorticoid and chemotherapy drugs is characterized in that the anticancer sustained release agent is a sustained release injection and consists of the following components:

(A) a sustained release microsphere comprising:

0.01-60% of anticancer active ingredient

Sustained release auxiliary materials 40-99.99%

0.0 to 30 percent of suspending agent

The above are weight percentages

And

Wherein,

the anticancer active ingredients are glucocorticoid and anticancer drugs selected from phosphoinositide 3-kinase inhibitor, pyrimidine analogue and/or DNA repair enzyme inhibitor;

the suspending agent is selected from one or more of sodium carboxymethylcellulose, iodoglycerol, dimethicone, propylene glycol, carbomer, mannitol, sorbitol, surface active substance, Tween 20, Tween 40 and Tween 80;

the viscosity range IV (dl/g) of the sustained-release auxiliary material is 0.1-0.8, and the sustained-release auxiliary material is selected from one or the combination of the following materials:

a) polylactic acid;

b) copolymers of polyglycolic acid and glycolic acid;

c) polifeprosan;

e) a di-fatty acid and sebacic acid copolymer;

f) poly (erucic acid dimer-sebacic acid) copolymer;

g) poly (fumaric acid-sebacic acid) copolymer;

h) xylitol, oligosaccharide, chondroitin, chitin, chitosan, hyaluronic acid, collagen, gelatin, poloxamer or protein glue;

The suspending agent has viscosity of 100-3000 cp (at 20-30 deg C), and is selected from one or more of sodium carboxymethylcellulose, hydroxymethyl cellulose, iodoglycerol, simethicone, propylene glycol, carbomer, mannitol, sorbitol, surfactant, Tween-20, Tween-40, and Tween-80.

2. The sustained-release anticancer injection according to claim 1, wherein the weight ratio of the glucocorticoid and the anticancer drug is 1-99: 1 to 1: 1-99.

3. The sustained-release injection for anticancer of claim 1, wherein the phosphoinositide 3-kinase inhibitor is selected from the group consisting of 7-hydroxy-astrosporin, 7-O-alkyl-astrosporin, β -methoxyastrosporin, alkylphosphocholine, hexadecylphosphocholine, octadecyl- (1, 1-dimethyl-4-piperidine) phosphate, 1-O-hexadecyl-2-O-methyl-rac-propanetriyl-3-phosphocholine, 1-O-octadecyl-2-O-methyl-sn-propanetriyl-3-phosphocholine, and, Inositol polyphosphate, cyclosporine A, tetradecyl phosphorylcholine, hexadecyl (N-N-N-trimethyl) hexanolamine phosphate, octadecyl phosphorylcholine, octadecyl- [2- (N-methyl piperidine) ethyl ] -phosphate or a combination thereof.

4. The sustained-release injection for anticancer according to claim 1, wherein the pyrimidine analog is selected from one of O4-benzylfolic acid, 2, 4, 5-triamino-6-benzyloxypyrimidine, 2, 4-diamino-6-benzyloxy-5-nitrosopyrimidine, 2, 4-diamino-6-benzyloxy-5-bromopyrimidine, 2-amino-4-benzyloxy-5-nitropyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitropyrimidine, 2, 4-diamino-6-benzyloxy-s-triazine, 2-amino-O4-benzylpteridine or a combination thereof.

5. The sustained-release anticancer injection according to claim 1, wherein the DNA repair enzyme inhibitor is selected from one or a combination of the following:

(a)2- (morphinan-4-yl) -chromen-4-yl, 2- (4-morpholino) -8-phenylchromone, 1- (2-hydroxy-4-morphinan-4-yl-phenyl) -ethanone, a kinase inhibitor, 2-aminopurine, 7-ethyl-10-hydroxycamptothecin, phenylbutyrate, methylamine, methoxyamine, hydroxylamine, minocycline, O-hydroxylamine, O-methylhydroxylamine or-O- δ -aminobutylhydroxylamine;

(b) 3-aminobenzamides, benzamides, 3, 4-dihydromethoxyisoquinoline-1 (2H) -benzamides, polymerase inhibitors, amino-substituted 2-arylbenzimidazole-4-carboxamides, benzimidazole-4-carboxamides, tricyclo-lactam hydrogensulfide, tricyclic benzimidazole carboxamides, benzimidazole, 1H-tricyclic benzimidazole carboxamide, 2-aryl-1H-benzimidazole-4-carboxamide, 2-phenyl-1H-benzimidazole-4-carboxamide, 2- (4-hydroxymethylphenyl) -1H-benzimidazole-4-carboxamide, 2- (3-methoxyphenyl) -1H-benzimidazole-4-carboxamide, and the like, 8-hydroxy-2-methylquinazolinone or 2- (4-hydroxyphenyl) benzimidazole-4-carboxamide;

(c) aminotriazoles, butylthioneoxime, puffball acid, S-hexyl glutathione, neopodophyllomycin, hexacyclic camptothecin or tetrarylcarboxamides.

6. The sustained-release anticancer injection according to claim 1, wherein the glucocorticoid is selected from one or a combination of them.

7. The sustained-release anticancer injection according to claim 1, wherein the sustained-release anticancer injection comprises the following active anticancer components in percentage by weight:

(2)0.1 to 10 percent of prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone or triamcinolone acetonide, 1 to 40 percent of O4-benzyl folic acid, 2, 4, 5-triamino-6-benzyloxy pyrimidine, a combination of 2, 4-diamino-6-benzyloxy-5-nitrosopyrimidine, 2, 4-diamino-6-benzyloxy-5-bromopyrimidine, 2-amino-4-benzyloxy-5-nitropyrimidine, 2-amino-4-benzyloxy-6-methyl-5-nitropyrimidine, 2, 4-diamino-6-benzyloxy-s-triazine, or-2-amino-O4-benzylpteridine; or

(3) 0.1-10% prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone or triamcinolone acetonide, and 1-40% imidazopiperazine, imidazopyridine, wortmannin, benzopyran, 6-aryl-2-morphinol-4-yl-pyran-4-yl, 2- (4-morpholino) -8-phenylchromone, 7-ethyl-10-hydroxycamptothecin, 3-cyano-6-hydrazonomethyl-5- (4-pyridyl) pyridine- [1H ] -2-1, phenylbutyric acid, methoxyamine, hydroxylamine, inositol polyphosphate, tetradecyl phosphorylcholine phosphate, hexakisdecyl (N-N-N trimethyl) hexanolamine phosphate, hexakis (N-N-N trimethyl) hexanolamine, Combinations of octadecyl phosphorylcholine, octadecyl- [2- (N-methylpiperidine) ethyl ] -phosphate, aminotriazole, or butylthionine sulfoximine.

8. The sustained-release anticancer injection according to claim 1, wherein the sustained-release excipients are selected,

(1) the molecular weight peak value of the polylactic acid is selected from 5000-10000, 10000-30000, 300000-60000, 60000-100000 or 100000-150000;

(2) in the copolymer of polyglycolic acid and glycolic acid, the ratio of polyglycolic acid to glycolic acid is 50-95: 50-50, and the peak value of molecular weight is 5000-10000, 100003-0000, 300000-60000, 600001-00000 or 100000-150000;

(3) in polifeprosan, the ratio of p-carboxyphenylpropane to sebacic acid is 10: 90, 20: 80, 30: 70, 40: 60, 50: 50 or 60: 40.

9. The sustained-release anticancer injection according to claim 1, wherein the suspending agent is one or a combination of the following:

a) 0.5-3.0% carboxymethylcellulose (sodium);

b) 5-15% mannitol;

c) 5-15% sorbitol;

d) 0.1-1.5% of surface active substances;

e) 0.1-0.5% tween 20;

f) iodoglycerol, dimethicone, propylene glycol or carbomer;

g) 0.5-5% of sodium carboxymethylcellulose and 0.1-0.5% of Tween 80;

h) 5-20% of mannitol and 0.1-0.5% of Tween 80; or

i)0.5 to 5 percent of sodium carboxymethylcellulose, 5 to 20 percent of sorbitol and 0.1 to 0.5 percent of Tween 80.

10. The sustained-release anticancer agent according to claim 1, wherein the sustained-release anticancer agent is a sustained-release implant, and the anticancer active ingredients thereof are:

The slow release auxiliary material is one or the combination of the following materials:

a) polylactic acid with the molecular weight peak value of 10000-;

b) a copolymer of polyglycolic acid and glycolic acid, wherein the ratio of polyglycolic acid to glycolic acid is 50-95: 50-50, and the peak value of molecular weight is 10000-30000, 300000-60000, 60000-100000 or 100000-150000;

d) polifeprosan, p-carboxyphenylpropane and sebacic acid at a ratio of 10: 90, 20: 80, 30: 70, 40: 60, 50: 50 or 60: 40;

e) a di-fatty acid and sebacic acid copolymer;

f) poly (erucic acid dimer-sebacic acid);

g) poly (fumaric-sebacic acid);

h) xylitol, oligosaccharide, chondroitin, chitin, chitosan, hyaluronic acid, collagen, gelatin, poloxamer or albumin glue;